Department of Pharmaceutical Sciences, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, People's Republic of China.
Green Pharmaceutical Technology Key Laboratory of Luzhou, School of Pharmacy, Southwest Medical University, Luzhou, 646000, People's Republic of China.
Int J Nanomedicine. 2024 Feb 23;19:1749-1766. doi: 10.2147/IJN.S427783. eCollection 2024.
Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer. However, the effect of current treatment strategies by inducing tumor cell apoptosis alone is not satisfactory. The growth, metastasis and treatment sensitivity of tumors can be strongly influenced by cancer-associated fibroblasts (CAFs) in the microenvironment. Effective cancer therapies may need to target not only the tumor cells directly but also the CAFs that protect them.
Celastrol and small-sized micelles containing betulinic acid were co-encapsulated into liposomes using the thin-film hydration method (CL@BM). Folic acid was further introduced to modify liposomes as the targeting moiety (F/CL@BM). We established a novel NIH3T3+4T1 co-culture model to mimic the tumor microenvironment and assessed the nanocarrier's inhibitory effects on CAFs-induced drug resistance and migration in the co-culture model. The in vivo biological distribution, fluorescence imaging, biological safety evaluation, and combined therapeutic effect evaluation of the nanocarrier were carried out based on a triple-negative breast cancer model.
In the present study, a novel multifunctional nano-formulation was designed by combining the advantages of sequential release, co-loading of tretinoin and betulinic acid, and folic acid-mediated active targeting. As expected, the nano-formulation exhibited enhanced cytotoxicity in different cellular models and effectively increased drug accumulation at the tumor site by disrupting the cellular barrier composed of CAFs by tretinoin. Notably, the co-loaded nano-formulations proved to be more potent in inhibiting tumor growth in mice and also showed better anti-metastatic effects in lung metastasis models compared to the formulations with either drug alone. This novel drug delivery system has the potential to be used to develop more effective cancer therapies.
Targeting CAFs with celastrol sensitizes tumor cells to chemotherapy, increasing the efficacy of betulinic acid. The combination of drugs targeting tumor cells and CAFs may lead to more effective therapies against various cancers.
三阴性乳腺癌（TNBC）是乳腺癌中最致命的亚型。然而，仅通过诱导肿瘤细胞凋亡的当前治疗策略的效果并不令人满意。肿瘤的生长、转移和治疗敏感性可以强烈受到微环境中癌症相关成纤维细胞（CAFs）的影响。有效的癌症疗法可能不仅需要直接针对肿瘤细胞，还需要针对保护它们的 CAFs。
采用薄膜水化法（CL@BM）将雷公藤红素和含有白桦脂酸的小尺寸胶束共同包封到脂质体中。进一步引入叶酸作为靶向部分（F/CL@BM）修饰脂质体。我们建立了一种新型 NIH3T3+4T1 共培养模型来模拟肿瘤微环境，并评估了纳米载体在共培养模型中对 CAFs 诱导的耐药性和迁移的抑制作用。基于三阴性乳腺癌模型，进行了纳米载体的体内生物分布、荧光成像、生物安全性评价和联合治疗效果评价。
在本研究中，通过结合顺序释放、同时载药、叶酸介导的主动靶向等优点，设计了一种新型多功能纳米制剂。正如预期的那样，纳米制剂在不同的细胞模型中表现出增强的细胞毒性，并通过破坏由维甲酸组成的细胞外基质有效地增加了药物在肿瘤部位的积累。值得注意的是，与单独使用任何一种药物的制剂相比，共载药纳米制剂在抑制小鼠肿瘤生长方面更有效，并且在肺转移模型中也显示出更好的抗转移效果。这种新型药物递送系统具有开发更有效癌症疗法的潜力。
用雷公藤红素靶向 CAFs 可使肿瘤细胞对化疗敏感，增加白桦脂酸的疗效。针对肿瘤细胞和 CAFs 的药物联合可能会导致针对各种癌症的更有效疗法。
